The therapeutic actions, as well as many of the neurological side effects, of antipsychotic drugs often take days to weeks and in some cases months to develop. However, until recently, most of what we knew about the mechanism and site of action of these drugs was derived from one dose experiments in which the effects were measured within a few hours after administration. Biochemical, behavioral and electrophysiological evidence derived from these acute experiments suggests that the CNS effects of antipsychotic drugs are primarily mediated through central dopaminergic systems. However, because of the time dependent nature of their clinical effects, the relevance of the acute data is questionable. The proposed research can be divided into two parts. One part continues to compare the effects of acute and chronic antipsychotic drug treatment on rat meso-telencephalic dopaminergic systems--both dopaminergic neurons themselves and neurons in the areas they innervate (e.g. caudate nucleus, accumbens nucleus, prefrontal cortex). Electrophysiological techniques will be used to examine the possibility that dopamine systems may differ in their response to acute and chronic treatment. Comparisons between drugs differing in their incidence of neurological side effects (e.g. haloperidol vs. clozapine) will also be made. The other set of experiments will use intracellular or extracellular single-unit-recording techniques to carry out in depth exploration of findings obtained during recently completed chronic studies. Observations to be studied further include the finding that chronic antipsychotic drug treatment causes nigral dopamine cells to stop producing action potentials and that parenterally administered haloperidol fails to block dopamine-induced inhibition of caudate neurons but nevertheless induces supersensitivity during chronic treatment. The information derived from these studies should further our knowledge of where and how antipsychotic drugs act in the brain. It is hoped that such information will ultimately lead to a greater understanding of the possible biological factors underlying psychosis, as well as the development of antipsychotic drugs with optimal antipsychotic properties and minimal neurological side effects.